RESUMEN
Chronic neonatal pulmonary hypertension frequently culminates in right ventricular (RV) failure and death. In juvenile rats, RV systolic dysfunction secondary to chronic hypoxia is rescued by systemic treatment with a Rho kinase (ROCK) inhibitor. To explore the relationship between ROCK inhibitor-mediated decreases in pulmonary vascular resistance and pressure, RV hypertrophy, and systolic dysfunction, we compared the effects of systemically administered to inhaled (pulmonary-selective) ROCK inhibitor on RV systolic function. Rat pups were exposed to air or hypoxia (13% O2) from Postnatal Days 1 to 21 and received rescue treatment with aerosolized fasudil (200 mM) for 15 minutes three times daily or intraperitoneal Y27632 (15 mg/kg twice daily) from Days 14 to 21. Chronic hypoxia differentially increased RhoA and ROCK activity in the right, but not left, cardiac ventricle. Inhaled ROCK inhibitor normalized pulmonary vascular resistance and caused regression of RV hypertrophy and pulmonary arterial wall remodeling but did not improve RV systolic dysfunction (decreased stroke volume and tricuspid annular plane systolic excursion). Systemic, but not inhaled, ROCK inhibitor normalized up-regulated ROCK and phosphodiesterase 5 activities in the right ventricle. Treatment with sildenafil (100 mg/kg/d intraperitoneally from Days 14 to 21) improved RV systolic function. Collectively, these data indicate that pressure unloading and regressed arterial and cardiac remodeling did not lead to recovery of systolic function while right ventricular ROCK activity remained increased. Right ventricle-specific up-regulation of RhoA/ROCK activity is critical to hypoxia-mediated systolic dysfunction, in part by regulating the activity of phosphodiesterase 5.
Asunto(s)
Hipertensión Pulmonar/enzimología , Hipertrofia Ventricular Derecha/enzimología , Disfunción Ventricular Derecha/enzimología , Quinasas Asociadas a rho/fisiología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/administración & dosificación , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Ventrículos Cardíacos/enzimología , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Hipertrofia Ventricular Derecha/etiología , Piperazinas/farmacología , Purinas/farmacología , Ratas , Citrato de Sildenafil , Sulfonamidas/farmacología , Resistencia Vascular/efectos de los fármacos , Disfunción Ventricular Derecha/tratamiento farmacológico , Disfunción Ventricular Derecha/etiología , Quinasas Asociadas a rho/antagonistas & inhibidores , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
Chronic pulmonary hypertension in the neonate and infant frequently presents with right-ventricular (RV) failure. Current clinical management may include protracted treatment with inhaled nitric oxide (iNO), with the goal of reducing RV afterload. We have previously reported that prolonged exposure to iNO causes RV systolic dysfunction in the chronic hypoxia-exposed juvenile rat, which was prevented by a peroxynitrite decomposition catalyst. Given that inhalation of CO2 (therapeutic hypercapnia) may limit oxidative stress and upregulated cytokine expression in the lung and other organs, we hypothesized that therapeutic hypercapnia would attenuate cytokine-mediated nitric oxide synthase (NOS) upregulation, thus limiting peroxynitrite generation. Sprague-Dawley rat pups were exposed to chronic hypoxia (13% O2) from postnatal day 1 to 21, while receiving iNO (20 ppm) from day 14 to 21, with or without therapeutic hypercapnia (10% CO2). Therapeutic hypercapnia completely normalized RV systolic function, RV hypertrophy, and remodeling of pulmonary resistance arteries in animals exposed to iNO. Inhaled nitric oxide-mediated increases in RV peroxynitrite, apoptosis, and contents of tumor necrosis factor (TNF)-α, interleukin (IL)-1α, and NOS-2 were all attenuated by therapeutic hypercapnia. Inhibition of NOS-2 activity with 1400 W (1 mg/kg/day) prevented iNO-mediated upregulation of peroxynitrite and led to improved RV systolic function. Blockade of IL-1 receptor signaling with anakinra (500 mg/kg/day) decreased NOS-2 content and had similar effects compared to NOS-2 inhibition on iNO-mediated effects, whereas blockade of TNF-α signaling with etanercept (0.4 mg/kg on alternate days) had no effects on these parameters. We conclude that therapeutic hypercapnia prevents the adverse effects of sustained exposure to iNO on RV systolic function by limiting IL-1-mediated NOS-2 upregulation and consequent nitration. Therapeutic hypercapnia also acts synergistically with iNO in normalizing RV hypertrophy, vascular remodeling, and raised pulmonary vascular resistance secondary to chronic hypoxia.